Process for a stable oil suspension



PROCESS FOR A STABLE OIL SUSPENSION Harold G. Garman, Kalamazoo, Mich., assignor to The UpiolmrCompany, Kalamazoo, Mich., a corporation of Michigan 7 No Drawing. Filed Jan. 3, 1957, Ser. No. 632,253 10 Claims. (Cl. 167-82) This invention relates to a manufacturing process and more particularly to a process for preparing oil suspensions for pharmaceutical use.

The development of suspensions for pharmaceutical use frequently depends on the chemical and physical properties of the ingredients to be suspended. It is oftentimes desirable to prepare oil suspensions of various solid, oil-' insoluble medicaments, especially where such medicaments are unstable in the usual aqueous vehicles.

A serious problem arises in the preparation of all pharmaceutical suspensions because of the lack of reliability of dosage. This unreliability of dosage results from the fact that many suspensions are'not homogeneous when actually used because the suspended ingredients settle. disproportionately and resuspend disproportionately or not at all. The inability to resuspend the ingredients of a suspension arises after the container has been station ary on the storage shelf for periods of time, has been transported in shipment or has been partially used by. the ultimate consumer. These several difiiculties have been severe enough in many cases that the settled'material has been practically impossible to resuspend because ofactua-lcaking at the bottom of the container.

The principal object of this invention is to prepare stable oil-suspensions of solid, oil-insoluble medicaments'that are suitable for pharmaceutical use. By stable suspensions are meant those in which the insoluble ingredients are suspended homogeneously throughout the vehicle for acceptable periods of time, and those. in which the suspension can be reconstituted to its original homogeneous form with relative ease once the insoluble ingredients have settled to a degree after longer periods of time or after transportation to points remote from the locale of manufacturing. A further object of this invention is to prepare pharmaceutically elegant suspensions intended for oral use that are suitable for the variable dosage'requirements' of children and acceptable to all users as to appearance, smoothness and taste. Other objects will be apparent to those skilled in the art to which this invention pertains.

These and related objects have been accomplished'by' the provision of a process which comprises the intimate mixing and blending of the principal solid ingredients to be suspended in the oil vehicle by simultaneous reduction to a suitable particle size prior to suspending said ingredients in the oil vehicle. Separate reduction of particle size for each of the ingredients, even though carried out to the same specifications, does not produce a satisfactory suspension. The reason for this is not understood, but empirical results indicate that the process of this invention is generally applicable to oil suspensions of pharmaceuticals. This intimate blending and simultaneous reduction of particle sizeare preferably brought-about by jetpulverizing techniques, e.g., air-micronizing, but are not" limited thereto since this step can be accomplished by other methods of comminution known in the art.

The term air-micronizing has reference to a method of reducing particle size by utilizing a jet of air under pressure in an enclosed chamber to bombard particles A 2,951,014 5 Patented Aug. 30, 1960 against one another and the internal surfaces of the chamber. As examples of said other means the following may be cited: micropulverizing, milling, triturating, and microatomizing. Further examples of the many ways in which comminution can be carried out can befound in Chapter 11 of Remingtons Practice of :Pharmacy, Eleventh Edition, Mack Publishing Company, 1956.

Although the preferred use of the invention is in the preparation of suspensions for oral use, it is not limited thereto since the process of the invention is suitable also for the preparation of suspensions for parenteral use, especially where high concentrations of the insoluble ingredients are involved.

Oil suspensions of many medicaments can be prepared by the process of this invention. For oral use, the following can be prepared: antibiotics, oil-insoluble vitamins, ephedrine, anti-histaminic agents, theophylline, sulfonamide drugs, barbituric acid compounds, lipotropic agents, analgesics, ferrous sulfate, and the like. For parenteral use the following can be so prepared: adrenocorticotropic hormone, vasopressin, oxytocin, epinephrine, oil-insoluble vitamins, chlorionic gonadotropin, heparin, and the like. For oral use, various flavors and sweeteners may be incorporated into the suspension. Preservatives are also desirable. For oral use, it may be advisable to use certain adjnvants such as acacia, pectin, magnesium oxide, magnesium stearate, kaolin, aluminum hydroxide, salts of alginic acid or tragacanth. Preferred ingredients of-the type referred to above are illustrated in the examples which follow.

The various solid ingredients to be suspended need not be in any special physical form prior to mixing and comminution, except with'reference to mechanical limitations of the comminution technique used. Most ingredients are available in the trade in suitable physical forms, but occa'sionally' aniii'g'redientmust be comminuted to a limited degree before being mixed with the other ingredients.

The comminution technique should be controlled to produce a suitable particle size of the ingredients to be suspended. Generally speaking, a suitable particle size isv prepared in accord withv the present invention as it is for individually processedl ingredients; As a practical matter particle size can only be expressed as to range and distribution of particles with-- the same for mixed ingredients in certain size limitations. These size limitations determine the particula'r'specific surface for the ingredients to be suspended and thereby the rheological properties of the finished suspension. The suitability of a given suspension is a functionof its rheological properties. However, as the present inventionindicates, the suitability of an. oil suspension of mixed ingredients for pharmaceutical use, is also a function of the manner in which the mixed ingredients are processed prior to suspension in the oil vehicle.

The acceptable range and distribution of particle size is 99 percent less than sixty microns and percent less than twenty microns. However, with respect to the preferred embodiments of the invention as illustrated by the examples, it is preferred that the range and distribution of particle size be 99 percent less than from about 45 to about twenty microns and 75 percent less than from about twenty to about five microns.

Any fixed oil suitable for pharmaceutical use can be utilized as the"vehicle for the suspension. Illustrative: oils include vegetable oils (such as sesame, cottonseed, peanut, olive, corn, coconut, and the like), synthetic oils,v and mineral oils. A gelling agent such as non-toxic saltsof the fatty acids (such as aluminum monostearate) can also be used to help stabilize the suspension.

The basic formula of theproducts to which the present for its perfection is as follows:

Principal ingredients:

For the purpose of evaluating the efiectiveness of this process in the preparation of oral suspensions, the procedure of shipping six to twelve containers of the various t 23 2x33 ingmdient 5 experimental suspensions by the usual means of truck @clamate Sodium and/ or freight car shipments to points at least 1500 miles Sweetener from the locale of manufacturing has been employed. fggfggigg Subsequently, said containers have been returned for ex- 7 Flavors 10 amination and testing. Examples illustrative of the Vehicle: diversified experiments, procedures and results are set A vegetable 011 forth in the following tables. A gelhng agent for said 011 TABLE I Sucrose, Oyclamate Identification percent Adjuvant Antibiotic Sodium, Oil Gelling Agent percent ISM-435 3t) Kelmar,3% KPenieillin G 2 Sesame Aluminum Mono- Stearatc, 0.5%. ET-loo do d0.-. 2 do Do. ET-162 2 D0. ET-287 2 Do.

Kelmar is Kelco Company's brand of potas contents of the above containers Powder processing details:

had caked badly slum alginate. After return from shipping destination, the

and resuspension was practically impossible. Sucrose mieropulverized. Oyclamate sodium and K penicillin G air-micronized separately. Kelmar not specially processed as to particle size.

TABLE II Sucrose, Gyclamate Identification percent Adjuvant Antibiotic Sodium, Oil Gelling Agent percent 10,702-32 3o Kelmar, 3%--- K Penicillin G.... 2 Sesame. Aluminum Mono- Kaolln, 10%.-- stearate, 1%.

10,702-33 30 0........... do 2 do Do.

After return from shipping destination, the contents of one container had eaked slightly and in the other were too thick.

Powder processing details: Sucrose separately. Kolmar not specially pro micropnlverized. Gyclamate sodium and K penicillin G air-micronized cessed as to particle size.

TABLE I11 Sucrose, Oyelamate Identification percent Adiuvant Antibiotic Sodium, Oil Gelling Agent percent 10,702-63 30 Kelmar,1% KPenicillin G 2 Sesame-.- Aluminum Monostearate, ll2%. 10,702-65 so Kelmar,2%.-- do 2 moo D0. 10,702-) 3U Kclmar,1% ---..-d0 2 do Aluminum M0110.

- stearate, 1.5%.

After return from shipping destinations, the contents of the above containers had plugged and shaking did not remove the plug. Powder proces separately. Kelm ing details: Sucrose micropulverized. Oyelamate sodium and K penicillin G eir-micronized or not specially processed as to particle size.

TABLE IV Sucrose, Cyclamate Identification percent Adiuvant Antibiotic Sodium, Oil Gelling Agent percent 10,702- 3o Kelmar,3% KPeniciliin o 2 Sesame Aluminum Monostearate, 2%. 10,702-81 30 do do 2 do Do. ,70 25 do do 2 .-.do Do.

After return from shipping destination, the contents of the'above containers were too thick and consider d sing details:

unsatisfactory.

Powder proces 8H. Sucrose, cyclamate processed as to particle size.

81. Sucrose and Kelmar air-microniz ed together.

separately. e 82. Sucrose an not specially processed as to particle size.

TABLE V Sucrose, Cyclamate Identification percent Adjuvant Antibiotic Sodium, Oil Gelling Agent percent 10,7026 20 Kaolin, 10% KPenicillin G 2 Cotton- Aluminum Monoseed. stearate, 1/2%. 10,702-7 20 do do 2 None. 10,702 30 None do 2 do; Aluminum Monostearate, 1/2%. 10,702-8- None Kaolin, 30%.. do 2 do D 10,702- None do do 2 do None.

After return from shipping destinations, the contents of the above containers had plugged or required shaking of the container after simple tilting, to resuspend.

Powder processing details: Sucrose micropulverized. Gyclamate sodium and K penicillin G air-micronlzed separately. Adjuvants not specially processed as to particle size.

TABLE VI Sucrose, v Cyclamate Identification percent Adjuvant Antibiotic Sodiuint, Oil GellingAgent percen 10,702-28 20 Kaolin, K Penicillin G 2 Sesame Aluminum Monostearate, 112%. 10,702-29 l5 Kaolin, 2 do. Do. 10,702-30 30 Kelmar,3% 2 Aluminum Monostearate, 1.5%.

After return from shipping destinations, the contents of the above containers had caked to various degrees and were considered unsatisfactory.

Powder processing details: Sucrose micropulverized. Cyclamate sodium and K pemcillin G air-micronized separately. Adjuvants not specially processed as to particle size.

TABLE V11 Sucrose, Cyclamate Identification percent Adjuvant Antibiotic Sodium, Oil Gelling Agent percent 10,70247 30 Kelmar,3%- KPenicillin G 2 Sesame Aluminum Monostearate, 1/2%. 10,702-48 do do 2 do Do.

' After return from shipping destinations, the contents of the above containers were too thick and/or had plugged to various degrees.

Powder processing details: Sucrose, cyclamate sodium and penicillin micronized separately. Kelmar not specially processed as to particle size.

TABLE VIII.

Sucrose, Cyclamate Identification percent Adjuvant Antibiotic Sodium, Oil Gelling Agent percent 10,702-74 K Penicillin G 2 Sesame Aluminum Monostearate, 112%.

A After return from shipping destinations, the contents of the above containers had plugged and could not be resuspended.

Powder processing details: Penicillin milled or micropulverized. Oyolamate sodium air-micronized. Sucrose Inicropulverized.

TABLE IX Sucrose, Cyclamate Identification percent Adjuvant Antibiotic Sodiun}; Oil Gelling Agent percen 10,702-57 Kelmar, 3%... KPenicillin G 2 Sesame Aluminum Monostearate, -1/2%.

10,702-58 20 do .do 2 do Do.

After return from shipping destinations, the contents of the above containers had plugged or were too thick. Powder processing details: Sucrose, cyclamate sodium andpemcillin Inicronized separately. Kelmar not processed specially as to particle size.

Thus, Tables I through IX show various oil suspensions in which the ingredients were varied insofar as practicable as to type, concentration and particle size, but in no case did these variations result in a product which would withstand the shipping test. As clearly shown by Table X-, only intimate mixing-bysimnltaneous -comminution of the principal ingredients .10 be suspended suspension capable of withstanding the shipping test prior to suspension in the oil vehicle resulted ,in an oil- TABLE X Cycla- Identification Sucrose, Adiuvant Antibiotic mate Oil Gelllng Agent percent Sodium, percent 25 Kelmar,3%. KPenicillin G..- 2 Sesame.- Aluminum Monostearate, 2%. 25 -do. 2 Do. 25 do 2 Do. 25 do 2 Do. 20 do.- 2 Do. 20 do. 2 Do. 22 Magnesium 2 Do.

stearate, 3%. 22 Magnesium 2 Do.

stearate, 5%.

After return from shipping destinations, the contents of each of the above containers could he resuspended by simple tilting of the container. Powder processing details:

All principal suspended ingredients mixed and then air-micronized together.

Similar experiments with other medicinal ingredients, e.g., tetracycline and novobiocln produced similar results. 7

The following data on particle size are taken from 0.025% vanillin powder U.S.P.

production type lots of satisfactory oil suspensions of potassium penicillin G for oral use.

Gil-154 GA-155 Oil-237 99% less than twenty 99% less than 99% less than forty microns. microns. microns. 75% less than ten 75% less than 75%1ess than twenty microns. twelve microns. microns.

The following data on particle size are taken from research type lots of satisfactory oil suspensions of potassium penicillin G for oral use.

11,097-1 and 2 11,096-5 and 6 11,0974 and 8 99% less than forty 99% less than thirty 99% less than 45 microns. microns. microns. 75% less than fifteen 75% less than 75% less than fifteen microns. fifteen microns. microns.

The following examples are illustrative of the process of this invention and are not to be construed as limiting.

Example 1 The following process is the preferred embodiment in the case of an oil suspension of potassium penicillin G for oral use.

Each milliliter contains:

0.005% coloring material 0.3% Saccharin soluble powder U.S.P.

2% cyclamate sodium 25% cane sugar granular U.S.P.

3% Kelmar dried (66,000 units) crystalline penicillin G potassium 0.2% flavors Q.s. sesame oil-aluminum monostearate 2% gel 99% less than fortymicrons 75% less than twenty microns Example 2 The following process is the preferred embodiment in theicase of an oil suspension of tetracycline for oral use.

Each milliliter contains:

0.007% coloring material 0.3% saccharin soluble powder U.S.P.

25 mg. tetracycline hydrochloride 2.5% cyclamate sodium 25% cane sugar granular U.S.P.

Q.s. aluminum monostearatesesame oil gel The coloring material is dissolved in the gel. The saccharin and vanillin are added and mixed well. The tetracycline, cyclamate sodium, and sugar are intimately mixed and blended together by air-micronization. The micronizcd mixture is added to the gel mixture. The flavors are added. The suspension is mixed thoroughly and passed through suitable dispersing equipment.

Particle size distribution of the air-micronized mixture:

7 99% less than ten microns 75% less than five microns Example 3 The following process is the preferred embodiment in the case of an oil suspension of novobiocin and a watersoluble salt of penicillin G for oral use.

Each milliliter contains:

0.3% saccharin soluble powder U.S.P.

2% cyclamate sodium 25% sugar granulated U.S.P.

3% Kelma-r dried (55,000 units) potassium penicillin G 27.5 mg. calcium acid novobiocin Q.s. seame oil-aluminum monos-tearate 2% gel The saccharin is added to the sesame oil-aluminum monostearate gel. The cyclamate sodium, sugar, Kelmar and penicillin are intimately mixed and air-micronized and added to the gel. The novobiocin acid calcium is added and the suspension is adjusted to volume with gel and processed through suitable dispersing equipment.

Particle size distribution of the air-micronized mixture:

99% less than twenty microns 75% less than ten microns Example 4 The following process is the preferred embodiment in the case of an oil suspension of salicylamide for oral use.

Each milliliter contains:

0.3% saccharin soluble powder U.S.P.

20% salicylamide 2% cyolamate sodium Q.s. cottonseed oil-aluminum monostearate 2% gel The saccharin is added to the sesame oil-aluminum monostearate gel. The cyclamate sodium and salicylamide are mixed, air-micronized and added to the gel. The suspension is adjusted to volume and processed through suitable dispersing equipment.

Particle size distribution of the air-micronized mixture:

99% less than thirty microns 75% less than fifteen microns The process of the invention can be utilized for the preparation of suspensions of other active ingredients and combinations of active ingredients, e.g., calcium acid novobiocin, penicillin and tetracycline, tetracycline and erythromycin, sulfa drugs, and sulfa drugs and novobiocin.

It is to be understood that the invention is not to be limited to the exact details of operation or compositions shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

I claim:

1. In the process of preparing a stable oil suspension for pharmaceutical use, the step which comprises the intimate mixing and blending of at least one active principal solid ingredient and a plurality of other principle solid ingredients to be suspended in an oil vehicle by simultaneous reduction in suitable particle size prior to suspension in said oil vehicle, the particle size to be 99% less than 60 microns.

2. In the process of preparing a stable oil suspension for pharmaceutical use, the step which comprises the intimate mixing and blending of at least one active principal solid ingredient and a plurality of other principal solid ingredients to be suspended in an oil vehicle by 30 10 simultaneous reduction in particle size prior to suspension in said oil vehicle, the particle size distribution to fall within the range of 99 percent less than sixty microns and 75 percent less than twenty microns.

3. The process of claim 2 in which the particle size distribution falls within the range of 99 percent less than from about to about twenty microns and percent less than from about twenty to about five microns.

4. The process of claim 2 in which the principal solid ingredients include an oil-insoluble salt of penicillin.

5. The process of claim 2 in which the principal solid ingredients include an oil-insoluble salt of tetracycline.

6. The process of claim 2 in which the principal solid ingredients include an oil-insoluble salt of novobiocin.

7. The process of claim 2 in which the principal solid ingredients include salicylamide.

8. The process of claim 2 in which the principal solid ingredients include sucrose, potassium alginate, sodium cyclamate, and a therapeutically active ingredient.

9. The process of claim 2 in which the vehicle comprises a vegetable oil and a gelling agent.

10. The process of claim 2 in which the vehicle comprises sesame oil and aluminum monostearate.

References Cited in the file of this patent UNITED STATES PATENTS 

1. IN THE PROCESS OF PREPARING A STABLE OIL SUSPENSION FOR PHARMACEUTICAL USE, THE STEP WHICH COMPRISES THE INTIMATE MIXING AND BLENDING OF AT LEAST ONE ACTIVE PRINCIPAL SOLID INGREDIENT AND A PLURALITY OF OTHER PRINCIPLE SOLID INGREDIENTS TO BE SUSPENDED IN AN OIL VEHICLE BY SIMULTANEOUSLY REDUCTION IN SUITABLE PARTICLE SIZE PRIOR TO SUSPENSION IN SAID OIL VEHICLE, THE PARTICLE SIZE TO BE 99% LESS THAN 60 MICRONS. 